Acute myeloid leukemia (AML) is a disease of the myeloid compartment of the hematopoietic system characterized by an accumulation of undifferentiated blast cells in the peripheral blood and bone marrow. AML is caused by multiple genetic and epigenetic changes that result in stimulation of mitogenic signals as well as deregulation of apoptosis and differentiation. It has been proposed that mutations in two different classes of oncogenes are required to induce AML. Mutations in class I oncogenes (e.g. Ras, Flt3) result in stimulation of proliferative and cell survival signals while mutations in class II oncogenes (e.g. AMLJ-Eto, PML-RARα) lead to inhibition of differentiation and subsequent cell death by apoptosis (Frohling S, et al., Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications, J. Clin. Oncol., 2005 Sep. 10; 23(26):6285-95; Gilliland, D. G., Hematologic malignancies Curr. Opin. Hematol., 2001 July; 8(4):189-91; Gilliland, D. G., Molecular genetics of human leukemias: New insights into therapy, Semin. Hematol., 2002 October; 39(4 Suppl 3):6-11). While many mutations are recurrently found in AML patients, it is believed that additional mutations in AML exist and have yet to be identified (Gilliland, D. G., Tallman, M. S., Focus on acute leukemias, Cancer Cell, 2002 June; 1(5):417-20; Deguchi, K., Gilliland, D. G., Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML, Leukemia, 2002 April; 16(4):740-4; Carnicer, M. J., et al., FLT3 mutations are associated with other molecular lesions in AML, Leuk. Res., 2004 January; 28(1): 19-23).
Screens have been performed to identify oncogenes in AML utilizing an efficient retroviral delivery, expression, and cDNA recovery system (Reuther, G. W., et al., RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia, J. Biol. Chem., 2002 Aug. 23; 277(34):30508-14; Reuther, G. W., et al., Identification and characterization of an activating TrkA deletion mutation in acute myeloid leukemia, Mol. Cell Biol., 2000 December; 20(23):8655-66). Using this approach, a novel activating deletion mutation was identified in the TrkA tyrosine kinase in a patient with AML (Reuther, G. W., et al., J. Biol. Chem., 2002 Aug. 23; 277(34):30508-14). This discovery provided the first evidence that TrkA may play a role in leukemogenesis. The deletion mutation identified has been shown to be leukemogenic in mice (Meyer J, et al., Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, [Delta]TrkA, Leukemia, 2007 October; 21(10):2171-80), further validating the approach to identify genes that contribute to leukemia formation.
Interleukin-27 (IL-27) was recently identified as a member of the IL-6/IL-12 family, and an important Th1 cytokine IL-27 is comprised of a helical subunit (p28) and a receptor-like protein related to IL12 p40, called Epstein-Barr induced gene 3 (EBI3). (Villarino, A. V., et al., IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chromic IBD, Int'l Immunol., 2008 June; 20(6):739-52; Owaki, T., et al., A role for IL-27 in early regulation of Th1 differentiation, J. Immunol., 2005 Aug. 15; 175(4):2191-200) IL-27 binds to TCCR, a heterodimer of IL-27R, also called WSX-1, and gp130, which are restricted to lymphoid and myeloid cells (Villarino, A. V., et al., Int'l Immunol., 2008 June; 20(6):739-52). Upon binding, IL-27 activates Jak1, -2, Stat1, -3, -4, -5, and TYK2, thereby inducing proliferation of naïve CD4+ cells, T-bet expression, and IL-12Rβ2 and IFN-γ expression (Lucas, S., et al., IL-27 regulates IL-12 responsiveness of naïve CD4+ T cells through Stat1-dependent and independent mechanisms, Proc. Nat'l Acad. Sci., 2003 Dec. 9; 100(25):15047-52; Owaki, T., et al., 2005 Aug. 15; 175(4):2191-200).
Even with a large knowledge base about the causative genetics of AML, a more complete understanding of the molecular players is needed to identify targets for future therapeutic treatment for this disease.